Is SKI p.His396Arg (c.1187A>G) pathogenic?

SKI p.His396Arg (c.1187A>G) is classified Likely benign in SKI (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-26). AlphaMissense: likely benign (0.1109); Ultra-rare (popmax 0.015%, amr); Associated with Shprintzen-Goldberg syndrome.

What condition is associated with SKI p.His396Arg (c.1187A>G)?

SKI p.His396Arg (c.1187A>G) is associated with Shprintzen-Goldberg syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SKI p.His396Arg (c.1187A>G) in the general population?

SKI p.His396Arg (c.1187A>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about SKI p.His396Arg (c.1187A>G)?

AlphaMissense predicts likely benign (score 0.1109) — an in-silico prediction, not a clinical call.

SKI p.His396Arg

c.1187A>G · rs987527805 · VCV582886

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Shprintzen-Goldberg syndrome

Computational evidence

Protein change
AlphaMissense	0.1109	likely benign
REVEL	0.335	indeterminate
SaProt	LLR -4.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.1	GERP 1.6, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 77 kb · p 0.0098 · regional, not allelic
Overall
CADD	19.88	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/59,946 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00205% 33/1,612,212 alleles · ultra-rare exomes 29/1,460,788 · genomes 4/151,424 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,661
European (non-Finnish)	0.00203%	49,159

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SKI
Protein: p.His396Arg
Coding: c.1187A>G
MANE Select: NM_003036
dbSNP: rs987527805
Type: single nucleotide variant
Location: chr1:2303376 (GRCh38)
Gene constraint: LOEUF 0.809 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.18 · 4 PDB

Full SKI gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Shprintzen-Goldberg syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

SKI p.His396= Likely benign ★★ same residue
SKI p.His396Asn Uncertain significance ★ ⚠ same residue
SKI p.His396Gln Uncertain significance ★ ⚠ same residue
SKI p.His396Tyr Uncertain significance ★ ⚠ same residue
SKI p.Gly116Glu Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly117Arg Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly117Ser Pathogenic/Likely pathogenic ★★ same condition
SKI p.Gly34Cys Pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ski-p-his396arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown